A Chemical Chaperone Decouples TDP-43 Disordered Domain Phase Separation from Fibrillation

Biochemistry
Kyoung-Jae ChoiAllan Chris M Ferreon

Abstract

Ribonucleoprotein (RNP) condensations through liquid-liquid phase separation play vital roles in the dynamic formation-dissolution of stress granules (SGs). These condensations are, however, usually assumed to be linked to pathologic fibrillation. Here, we show that physiologic condensation and pathologic fibrillation of RNPs are independent processes that can be unlinked with the chemical chaperone trimethylamine N-oxide (TMAO). Using the low-complexity disordered domain of the archetypical SG-protein TDP-43 as a model system, we show that TMAO enhances RNP liquid condensation yet inhibits protein fibrillation. Our results demonstrate effective decoupling of physiologic condensation from pathologic aggregation and suggest that selective targeting of protein fibrillation (without altering condensation) can be employed as a therapeutic strategy for RNP aggregation-associated degenerative disorders.

Citations

Dec 28, 2018·Chemistry : a European Journal·Emily P BentleyAshok A Deniz
Feb 23, 2019·Biomolecules·Taranpreet KaurPriya R Banerjee
Mar 1, 2019·The Journal of Biological Chemistry·W Michael BabinchakWitold K Surewicz
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Nov 6, 2020·Nature Communications·W Michael BabinchakWitold K Surewicz
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May 6, 2021·International Journal of Molecular Sciences·Alistair WoodSarah Lyn Rea
May 11, 2021·International Journal of Biological Macromolecules·Katarzyna SołtysAndrzej Ożyhar
May 14, 2021·Protein Science : a Publication of the Protein Society·Phoebe S TsoiAllan Chris M Ferreon

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